Transcript L 4 Parkinsondiseas..

Drugs used in
Parkinson disease
Epidemiology
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Average age of onset 62.5
Men and women affected equally
Genetic Link
African-Americans and Asians less likely
than Caucasians to develop Parkinson’s
Caffeine and smoking shows some
protective effects
Pathogenesis
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Four Theories
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Oxidative damage
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Environmental toxins
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MPTP-Methyl-phenyl tetrahydropyridine
Genetic predisposition
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Impaired protection
Mutations in the gene for the protein alpha-synuclein
located on chromosome 4
Accelerated aging
Pathophysiology
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Imbalance of dopamine and acetylcholine
Loss of 80 to 90% of dopaminergic
production in the substantia nigra
Lewy Bodies
Degeneration of dopaminergic neurons in the
substantia nigra.
Dopamine
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Symptoms caused by insufficient dopamine.
3 main symptoms:
Tremors
Rigidity
Slowed motion (Bradykinesia)
Other symptoms include:
Dementia, sleep disturbances, depression, etc.
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Degenerative disease of the basal ganglia causing tremor at
rest, muscle rigidity hypokinesia, often with dementia.
Associated with aggregation of α-synuclein (a protein normally
involved in vesicle recycling) in the form of characteristic Lewy
bodies.
Often idiopathic but may follow stroke or virus infection; can
be drug-induced (neuroleptic drugs). Rare familial forms also
occur, associated with various gene mutations, including αsynuclein.
Associated with early degeneration of dopaminergic
nigrostriatal neurons, followed by more general
neurodegeneration.
Can be induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), a neurotoxin affecting dopamine
neurons. Similar environmental neurotoxins, as well as genetic
factors, may be involved in human Parkinson's disease.
PARKINSON'S
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is a progressive disorder of movement that occurs
mainly in the elderly. The chief symptoms are:
tremor at rest, usually starting in the hands which
tends to diminish during voluntary activity
muscle rigidity, detectable as an increased
resistance in passive limb movement
suppression of voluntary movements
(hypokinesis), due partly to muscle rigidity and
partly to an inherent inertia of the motor system,
which means that motor activity is difficult to stop
as well as to initiate .
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Parkinsonian patients walk with a
characteristic shuffling gait. They find it
hard to start, and once in progress they
cannot quickly stop or change direction. PD
is commonly associated with dementia,
probably because the degenerative process
is not confined to the basal ganglia but also
affects other parts of the brain .
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Parkinson's disease often occurs with no
obvious underlying cause, but it may be the
result of cerebral ischaemia, viral
encephalitis or other types of pathological
damage.
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The symptoms can also be drug-induced,
the main drugs involved being those that
reduce the amount of dopamine in the brain
(e.g. reserpine) or block dopamine receptors
(e.g. antipsychotic drugs such as
chlorpromazine;).
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There are rare instances of early-onset PD
that runs in families, and several gene
mutations have been identified, the most
important being synuclein and parkin. Study
of these gene mutations has given some
clues about the mechanism underlying the
neurodegenerative process
Pathophysiology
Motor system-fine balance of inhibitory and
excitatory inputs of basal ganglia and cerebellum
Cerebellar output is excitatory, basal ganglia is
inhibitory
Pathophysiology
Apoptosis of dopaminergic neurons in substantia
nigra-leads to decrease in inhibition
Disruption of signals to motor cortex via thalamus
Smooth, coordinated movement is lost
Neurotoxins
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In 1982, a group of young drug addicts in California
suddenly developed an exceptionally severe form of PD
(known as the 'frozen addict' syndrome), and the cause was
traced to the compound 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), which was a contaminant in a
preparation used as a heroin substitute .
MPTP causes irreversible destruction of nigrostriatal
dopaminergic neurons in various species, and produces a
PD-like state in primates. MPTP acts by being converted to
a toxic metabolite, MPP+, by the enzyme monoamine
oxidase (MAO, specifically by the MAO-B subtype).
MPP+ is taken up by the dopamine transport system, and
thus acts selectively on dopaminergic neurons; it inhibits
mitochondrial oxidation reactions, producing oxidative
stress
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MPTP appears to be selective in destroying nigrostriatal
neurons and does not affect dopaminergic neurons
elsewhere-the reason for this is unknown.
Selegiline , a selective MAO-B inhibitor ,prevents MPTPinduced neurotoxicity by blocking its conversion to MPP+.
Selegiline is also used in treating PD as well as inhibiting
dopamine breakdown, it might also work by blocking the
metabolic activation of a putative endogenous, or
environmental, MPTP-like substance, which is involved in
the causation of PD. It is possible that dopamine itself
could be the culprit, because oxidation of dopamine gives
rise to potentially toxic metabolites.
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Whether or not the action of MPTP reflects the
natural pathogenesis of PD, the MPTP model is a
very useful experimental tool for testing possible
therapies.
Various herbicides, such as rotenone, that
selectively inhibit mitochondrial function cause a
PD-like syndrome in animals, suggesting that
environmental toxins could be a factor in human
PD, because impaired mitochondrial function is a
feature of the disease in humans.
What is an animal model?
A laboratory animal used in research that simulates
processes comparable to those that occur in humans.
Two common animal models.
Lab rats.
Fruit flies.
Vertebrate model
Invertebrate model
Somehow resistant to MPTP
Dopamine is depleted.
Rotenone administered
systemically Chronic nigrostriatal cell loss,
dopamine
depletion, Akinesia, rigidity,
tremor, flexed posture,
piloerection.
But is reversible by Hsp70
coexpression.
Is there any use for this in
human model?
Pharmacotherapy
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Levodopa
Dopamine agonists
COMT inhibitors
Amantadine
Anticholinergics
MAO-B inhibitor ex. Selegiline, Rasagiline
Drugs used in Parkinson'sdisease
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Drugs act by counteracting deficiency of
dopamine in basal ganglia or by blocking
muscarinic receptors. None of the available
drugs affect the underlying
neurodegeneration.
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Drugs include:
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levodopa (dopamine precursor;), given with an
inhibitor of peripheral dopa decarboxylase (e.g.
carbidopa ) to minimise side effects; sometimes
a catechol-O-methyltransferase inhibitor (e.g.
entacapone ) is also given, especially to patients
with 'end of dose' motor fluctuations
bromocriptine (dopamine agonist;)
 selegiline (monoamine oxidase B inhibitor)
 amantadine (which may enhance dopamine
release)
 benztropine (muscarinic receptor antagonist
used for parkinsonism caused by antipsychotic
drugs).
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Neurotransplantation, still in an
experimental phase, may be effective but
results are variable.
levodopa
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Dopamine is a neurotransmitter as well as being the
precursor for noradrenaline. It is degraded in a similar
fashion to noradrenaline, giving rise mainly to
dihydroxyphenylacetic acid and homovanillic acid,
which are excreted in the urine.
There are three main dopaminergic pathways:
 nigrostriatal pathway, important in motor control
 mesolimbic/mesocortical pathways, running from
groups of cells in the midbrain to parts of the
limbic system, especially the nucleus accumbens,
and to the cortex; they are involved in emotion and
drug-induced reward systems
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tuberohypophyseal neurons running from the
hypothalamus to the pituitary gland, whose
secretions they regulate
levodopa
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levodopa (dopamine precursor;), given with
an inhibitor of peripheral dopa
decarboxylase (e.g. carbidopa ) to minimise
side effects; sometimes a catechol-Omethyltransferase inhibitor (e.g. entacapone
) is also given, especially to patients with
'end of dose' motor fluctuations
Levodopa
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L-Dopa (Larodopa by Roche)
Introduced in the late 1960s
Crosses the blood-brain barrier
Adverse effects such as nausea, vomiting,
postural hypotension, involuntary
movements, restlessness, and cardiac
arrhythmias
Dopamine Agonists
“Synthetic Dopamine”
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Bromocriptine Mesylate (Parlodel)
Pergolide Mesylate (Permax)
Pramipexol (Mirapex)
Ropinirole HCL (Requip)
Rotigotine
Dopamine Agonists
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Monotherapy or combination
Are particulary usefull for:
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Prolonging the effective treatment period in patients with
deteriorating response.
Delaying the onset of L-dopa therapy. Particularly in younger
patients.
Treating patients who cannot tolerate high doses of L-dopa.
Associated with more side effects than L-dopa
Potential adverse effects include somnolence, dyskinesias,
nausea, vomiting, orthostatic hypotension, nightmares,
hallucinations, confusion, dizziness
COMT Inhibitors
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Entacapone (Comtan)
Tolcapone (Tasmar)
COMT Inhibitor
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Entacapone (Comtan)
Adjunct therapy
 Initial dose of 200mg with each dose of
levodopa up to 8 times daily
 Decrease of L-dopa may be necessary
 Exacerbation of L-dopa side effects , diarrhea,
urine discoloration, abdominal pain
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COMT Inhibitor
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Tolcapone (Tasmar)
Adjunct therapy
 Initial 100mg TID up to 200mg TID
 More potent and longer acting than entacapone
 Decrease L-dopa by 25 to 50%
 Exacerbation of L-dopa side effects, diarrhea,
urine discoloration, liver toxicity.
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Amantadine
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Amantadine HCL (Symmetrel)
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Inhibits dopamine recapture
Blocks acetylcholine and glutamate receptors
Dose 100mg BID to TID
Caution in renal failure patients
Currently used to reduce choreic movements
Narrow therapeutic range
Unpleasant side effects such as nausea, dizziness,
confusion, hallucinations, nightmares, dry mouth
peripheral edema.
Anticholinergics
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Trihexyphenidyl HCL (Artane)
Benztropine Mesylate (Cogentin)
Monotherapy or adjunct
 most effective for reducing tremor
 Use Limited by side effects especially in the
elderly.
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Anticholinergics
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Trihexyphenidyl HCL (Artane)
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Initial dose of 1mg and increase by 2 mg every 3 to 5 days until 6 to
10 mg/day. Usually given TID with meals or QID with meals and
at bedtime.
Possible adverse effects include dry mouth, blurred vision,
somnolence, hallucinations, memory impairment, confusion,
urinary retention, and constipation.
Benztropine Mesylate (Cogentin)
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Initial dose of 0.5 to 1 mg at bedtime. Increase by 0.5mg every 5 to 6
days up to a total daily dosage of 6mg.
Possible adverse effects include dry mouth, blurred vision,
somnolence, hallucinations, memory impairment, confusion,
urinary retention, and constipation.
Selegiline
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Selegiline HCL(Eldepryl)
Selegiline
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Selegiline HCL (Eldepryl)
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Monotherapy or adjunct
MOA-inhibits monoamine oxidase-B (MAO-B)
Inhibition of MAO-A does not occur
Dosage of 5 mg BID with breakfast and lunch
When used as monotherapy delays the need of L-dopa
by an average of nine months.
Possible adverse effects include nausea, dizziness,
abdominal pain, confusion, and exacerbation of L-dopa
side effects
Controversial theory of decreased rate of neuronal death
due to a reduction of free radicals.
Surgical Options
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Pallidotomy and Pallidal Stimulation
Thalamotomy and Thalamic Stimulation
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Introduced in 1950
Pallidotomy improves tremor, rigidity, and bradykinesia
Thalamotomy relieves tremor, rigidity, but not
bradykinesia
Neurosurgical treatment came to a end with the
introduction of L-dopa in late 1960s
Resurgence of neurosurgical intervention with the
failure of pharmacological treatments after 10 to 15 years
of disease progression
Two methods: Ablation and deep brain stimulation
Surgery Deep Brain Stimulation
Brain pacemaker, sends electrical impulses to brain to
stimulate the subthalamic nucleus.
Improves motor functions and reduce motor
complications.
Complications include: brain
hemorrhage, seizures, death.
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Surgery...
Deep Brain Stimulation (DBS)
Reduces distressing symptoms such as rigidity.
Tiny wire electrodes are implanted in the Basal Ganglia. They are connected to an
Implantable Pulse Generator in the chest.
Turn pulse on:
Turn pulse off:
symptoms reduce.
symptoms return.
Cost €40,000 to €50,000!
Ideal candidates are younger and fit. Must have no history of severe depression.
Grafting
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Suprarenal to brain transplantation
Fetal tissue transplantation
Cell culture transplantation
Under Investigation
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Implantable pumps
Implantable capsules containing dopamineproducing cells
New medications to target one of the five
individual brain receptors for dopamine
Continued genetic research
What does the future hold?
Stem cell research...
scientists are creating dopamine-producing neural cells.
These can be injected into patients brain to reverse the effects of Parkinson's.
BUT - Will the injected cells be accepted by the patient?
Or will they be destroyed in a natural immune response.
This research is ongoing. It may take 20 years before it is ready for widespread use.